Tissue inhibitor of metalloproteinases-1 induces a pro-tumourigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes

• Published in: Oncogene 2015-07, Vol.34 (28), p.3640-3650
• Main Authors: Cui, H, Seubert, B, Stahl, E, Dietz, H, Reuning, U, Moreno-Leon, L, Ilie, M, Hofman, P, Nagase, H, Mari, B, Krüger, A
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/106; 13/89; 13/95; 14/19; 14/28; 38/77; 45/90; 631/80/86/2366; 64/60; Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma of Lung; AKT protein; Angiogenesis; Animals; Apoptosis; Cancer; CD63 antigen; Cell Biology; Cell Line, Tumor; Cells; Endothelial cells; Exosomes; Exosomes - genetics; Exosomes - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic; Health aspects; HEK293 Cells; Human Genetics; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-inducible factor 1a; Inhibitor drugs; Internal Medicine; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Matrix metalloproteinase; Medicine; Medicine & Public Health; Metastases; Mice; MicroRNAs - genetics; miRNA; Neoplasm Transplantation; Oncology; original-article; Phosphorylation; Prognosis; Proteins; Rad52 protein; Signal Transduction; Tissue inhibitor of metalloproteinase 1; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissues; Tumors; Umbilical vein; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.300

Tissue inhibitor of metalloproteinases-1 (TIMP-1) recently emerged as a pro-metastatic factor highly associated with poor prognosis in a number of cancers. This correlation seemed paradox as TIMP-1 is best described as an inhibitor of pro-tumourigenic matrix metalloproteinases. Only recently, TIMP-1 has been revealed as a signalling molecule that can regulate cancer progression independent of its inhibitory properties. In the present study, we demonstrate that an increase of both exogenous and endogenous TIMP-1 led to the upregulation of miR-210 in a CD63/PI3K/AKT/HIF-1-dependent pathway in lung adenocarcinoma cells. TIMP-1 induced P110/P85 PI3K-signalling and AKT phosphorylation. It also led to increase of HIF-1α protein levels positively correlating with HIF-1-regulated mRNA expression and upregulation of the microRNA miR-210. Downstream targets of miR-210, namely FGFRL1, E2F3, VMP-1, RAD52 and SDHD, were decreased in the presence of TIMP-1. Upon the overexpression of TIMP-1 in tumour cells, miR-210 was accumulated in exosomes in vitro and in vivo . These exosomes promoted tube formation activity in human umbilical vein endothelial cell (HUVECs), which was reflected in increased angiogenesis in A549L-derived tumour xenografts . Activation and elevation of PI3K, AKT, HIF-1A and miR-210 in tumours additionally confirmed our in vitro data. This new pro-tumourigenic signalling function of TIMP-1 may explain why elevated TIMP-1 levels in lung cancer patients are highly correlated with poor prognosis.